GH-Secreting Adenoma or Tumor? Issues in Pituitary Neoplasms Nomenclature, Classification, and Characterization.

GH-secreting pituitary adenomas are nearly always visible on conventional magnetic resonance (MR) imaging. However, management and outcome of acromegalic patients lacking imaging evidence of GH-secreting pituitary adenomas are undefined. The aim was to evaluate surgical exploration for MR-invisible GH-secreting pituitary adenomas. We conducted a retrospective review at two tertiary care centers. Consecutive acromegalic patients without imaging evidence of a pituitary adenoma on pre- and postcontrast, spin echo T1-weighted MR imaging and who lacked evidence of an ectopic (nonpituitary) source causing GH excess were included. Surgical exploration with identification and resection of a pituitary adenoma was performed. Laboratory values (GH, IGF-I), surgical findings, and clinical outcome were analyzed. Six patients (three males, three females; 3% of all patients) with suspected GH-secreting adenomas did not demonstrate imaging evidence of pituitary adenoma on conventional MR imaging. Three patients underwent a postcontrast, volumetric interpolated breath-hold examination MR-imaging sequence (1.2-mm slice thickness), which revealed a 4-mm pituitary adenoma not seen on the spin echo T1-weighted MR imaging in one patient. A pituitary adenoma was identified and removed in all patients (mean diameter, 5.6 mm; range, 5 to 6.7 mm). Histological analysis confirmed that the lesions were GH-secreting adenomas. All patients achieved biochemical remission after surgical resection. Acromegaly can be caused by GH-secreting pituitary adenomas that are not evident on conventional MR imaging. Adenomas in some of these patients become evident using volumetric interpolated breath-hold examination MR imaging. Surgical exploration of the pituitary gland in acromegalic patients with endocrine findings consistent with a GH-secreting adenoma but negative MR imaging can lead to identification and removal of an adenoma.

The molecular events leading to the development of GH-secreting pituitary tumours remain largely unknown. Gsalpha (GNAS1) mutations are found in 27-43% of sporadic GH-secreting adenomas in the Caucasian population, but the frequency of GNAS1 mutations in Japanese and Korean acromegalic patients was reported to be lower, 4-9% and 16%, respectively. Other genes responsible for the tumourigenesis of GH-secreting pituitary adenomas have not been detected yet. PRKAR1A, which codes for the RIalpha regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) on 17q23-24, was recently reported to contain inactivating mutations in some Carney complex families, which involved GH-secreting adenomas in about 10%. We re-evaluated the frequency of GNAS1 mutations and investigated PRKAR1A on the hypothesis that it might play a role in the tumourigenesis of GH-secreting adenomas. We analysed exons 8 and 9 of GNAS1 and all exons and the exon-intron boundaries of PRKAR1A with the PCR and by direct sequencing using genomic DNA extracted from 32 GH-secreting pituitary adenomas (30 GH-secreting adenomas, two GH and PRL-secreting adenomas) and 28 corresponding peripheral blood samples, and performed loss of heterozygosity (LOH) analysis of 17q23-24 with four microsatellite markers and intragenic markers of PRKAR1A. Seventeen of 32 (53.1%) tumours showed somatic-activating mutations of GNAS1: 16 (53.3%) of 30 GH-secreting adenomas and one of two GH and PRL-secreting adenomas. Neither inactivating somatic mutations of PRKAR1A nor LOH of 17q23-24 were detected in any of the tumours examined. We reconfirm the important role of activating mutations of GNAS1 in GH-secreting adenomas, and conclude that PRKAR1A does not play a significant role in the tumourigenesis.

Growth hormone-releasing hormone (GHRH) stimulates not only the synthesis and secretion of GH but also the proliferation of normal somatotrophs. The expression of GHRH receptor (GHRHR) is regulated by GHRH, both of which are known to be expressed in human GH-secreting pituitary adenoma cells. Somatic mutations in the subunit of Gsalpha protein (gsp), lead to the constitutive activation of adenylyl cyclase in pituitary adenomas that secrete GH. It has not been examined how gsp mutations influence GHRHR expression in GH-secreting adenomas. We therefore analyzed the expression levels of GHRHR messenger ribonucleic acid (mRNA) in GH-secreting pituitary adenomas focusing on a gsp mutation. Furthermore, we investigated the effect of GHRH on the expression of GHRHR mRNA in primary cultures of GH-secreting pituitary adenoma cells. GHRHR mRNA expression levels were significantly elevated in gsp mutation-positive GH-secreting adenomas compared with those in gsp mutation-negative ones. In primary-cultured GH-secreting adenoma cells, the increase of GH secretion in response to GHRH was shown in both gsp mutation-positive and -negative adenoma cells with a significantly higher response in the latter adenoma cells. GHRH increased GHRHR mRNA expression level in gsp mutation-negative adenoma cells while it was not influenced by GHRH in gsp mutation-positive adenoma cells. These results suggest that gsp mutations up-regulate GHRHR mRNA expression in GH-secreting pituitary adenoma cells, and that gsp mutations desensitize the adenoma cells to GHRH in terms of their GHRHR mRNA expression probably because of their saturation of GHRH signaling.

Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome sequencing (n=36). By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed. This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.

Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

The efficacy of dopaminergic agents in the medical treatment of pituitary adenomas is well known. Quinagolide is a nonergot derivative dopamine agonist, which binds dopamine D2 receptors with high affinity. The treatment with this drug is reported to suppress hormone levels and to cause tumor shrinkage in prolactinomas and in a few GH-secreting pituitary adenomas. In clinically nonfunctioning pituitary adenomas (NFPA), the efficacy of quinagolide treatment is controversial. The scintigraphy of the pituitary region using 123I-methoxybenzamide (123I-IBZM) allows us to visualize in vivo the expression of dopamine D2 receptors on pituitary tumors. In this study, the pituitary scintigraphy with 123I-IBZM was performed in 14 patients with macroadenoma before starting a long-term treatment with quinagolide: 6 NFPA with high circulating alpha-subunit levels, 4 PRL-secreting, and 4 GH-secreting adenomas. A 3-point score was used to grade the ligand accumulation within the pituitary adenomas: 0 = negative, 1 = moderate uptake (equal to that recorded in the cerebral cortex), and 2 = intense uptake (equal to that recorded in the basal nuclei). The treatment with quinagolide was carried out at the dose of 0.3-0.6 mg/day for 6-12 months. Clinical, biochemical and hormonal assessment was repeated monthly during the first 3 months, then quarterly. Sellar magnetic resonance imaging was performed before and after 6 and 12 months of quinagolide treatment, to evaluate tumor shrinkage (> 25% of baseline size). In all 14 patients, a significant positive correlation was found between the degree of 123I-IBZM uptake and the clinical response to quinagolide treatment (r = 0.90; P < 0.001). In particular, the normalization of serum alpha-subunit and PRL levels, respectively, was achieved in 3 patients with NFPA and in 2 patients with prolactinoma, who showed intense 123I-IBZM uptake in the pituitary region. In 4 of these 5 patients with positive scan, a significant tumor shrinkage occurred between 6 and 12 months after the beginning of quinagolide treatment. In all patients with GH-secreting adenoma, no significant uptake of 123I-IBZM was found and no significant decrease of circulating GH and/or insulin-like growth factor-I levels, and tumor shrinkage was obtained during long-term treatment with quinagolide. In conclusion, the pituitary scintigraphy with 123I-IBZM can be considered a useful tool to indicate adenomas with significant expression of functioning D2 receptors. This innovative technique may predict the response to long-term treatment with quinagolide in patients with NFPA, where the lack of pituitary hormone hypersecretion makes difficult the monitoring of medical treatment efficacy.

BackgroundIn more than 98% of cases, acromegaly is due to a GH-secreting pituitary adenoma. The term “ectopic acromegaly” includes neuroendocrine tumors secreting GH releasing hormone (GHRH), usually located in the lungs, thymus and endocrine pancreas. Considerably less frequent are cases of ectopic acromegaly due to GH-secreting tumors located out of the pituitary fossa; except for one isolated case of a well-documented GH-secreting lymphoma, the majority of these lesions are located in the sphenoid sinus.Case presentationWe present the case of a 45 year old woman with acromegaly whose MRI showed an empty sella without evidence of a pituitary adenoma but revealed a large mass within the sphenoid sinus. She underwent transsphenoidal surgery and the excised sphenoid sinus mass, proved to be a GH-secreting adenoma; the sellar floor was intact and no other lesions were found in the pituitary fossa. She required postoperative treatment with somatostatin analogs and cabergoline for clinical and biochemical control.ConclusionsThis case highlights the importance of carefully evaluating the structures surrounding the sellar area when a pituitary adenoma is not found with currently available imaging techniques. The finding of an intact sellar floor and duramater lead us to conclude that the patient’s tumor originated de novo from embryological pituitary remnants. Upon a careful review of the literature and a critical evaluation of our case we found neither clinical nor biochemical features that would distinguish an ectopic from the more common eutopically located somatotrophinoma.

Seladin-1 (from selective Alzheimer's disease indicator-1) is a recently discovered gene that has been found to be down-regulated in brain regions affected by Alzheimer's disease. Seladin-1 effectively protects neurons against beta-amyloid-mediated toxicity and prevents apoptosis via inhibition of the activation of caspase-3, a key mediator of the apoptotic cascade. Although seladin-1 is expressed in the pituitary gland, no study addressed the expression or the function of this gene in pituitary adenomas. The aim of the present study was to determine the expression level of the seladin-1 gene in pituitary tumors, i.e. GH-secreting and nonfunctioning pituitary adenomas (NFPA), and to determine whether differential expression might be associated with different somatostatin (sst)-induced apoptosis. We found by quantitative real-time RT-PCR that the expression level of seladin-1 was significantly higher in NFPA (n = 21) than in GH-secreting adenomas (n = 30; mean +/- se, 25.69 +/- 6.39 vs. 8.02 +/- 2.68 pg/microg total RNA; P = 0.006). Although the amount of activated caspase-3 did not differ between the two groups of tumors, in primary cell cultures, octreotide was able to increase apoptosis, evaluated by the level of cleaved cytokeratin 18 and the presence of apoptotic nuclei, in GH-secreting adenomas, but not in NFPA. This different response was not attributable to differences in the amount of transcript of sst receptors 2 and 5, which was similar in the two groups of tumors. Our results suggest that differential seladin-1 expression in pituitary adenomas may be associated with a different apoptotic response to sst analogs.

To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells. Octreotide-treated patients showed a lower Ki-67 LI (1.8 +/- 0.3%) than untreated controls (3.8 +/- 0.7%; P < 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 +/- 0.2% and 0.8 +/- 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P < 0.03). Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.

To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA). Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry. There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERβ gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERβ protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERβ, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04). GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERβ, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

To explore the clinical characteristics of pituitary adenomas in patients with MEN1 and to summarize treatment strategies for MEN1 in a Chinese population. We retrospectively analyzed 54 MEN1 patients with pituitary adenomas diagnosed at Peking Union Medical College Hospital from March 2003 to January 2017. Clinical data, laboratory testing results, treatments of involved glands and treatment responses were collected and analyzed. The mean age at pituitary adenoma diagnosis was 53.9 ± 17.8. The patients initially consulted the Endocrinology, General Surgery and Neurosurgery departments, in descending frequency. The nonfunctioning adenoma, prolactinoma, GH-secreting adenoma, cosecreting adenoma, and ACTH-secreting adenoma subtypes accounted for 48.1%, 27.8%, 9.3%, 9.3% and 5.6% of the cases, respectively. The remission rate for prolactinomas was 46.2% (6/13) treated with bromocriptine. And the remission rates were 87.5% (7/8) and 100% (3/3) for GH-secreting adenomas and ACTH-secreting adenomas respectively achieved by transsphenoidal surgery. Nineteen (35.2%) patients with asymptomatic nonfunctioning pituitary adenomas showed no progression after a 35-month follow-up with close observation. Regarding treatment priority, patients with thymic carcinoid tumors received first-line surgery, 54% of the patients with enteropancreatic tumors had these tumors treated first, and 26% of all patients had their pituitary adenomas treated first. In acromegalic patients, pituitary lesions tended to be treated first (75%, p = 0.002). PHPT and adrenocortical adenomas can be managed with elective surgery. The treatment of MEN1 requires cooperation between multidisciplinary teams. Individualized treatment according to the severity of glandular involvement is needed. GH-secreting and ACTH-secreting pituitary adenomas require active treatment, while nonfunctioning pituitary adenomas can be observed closely.

BackgroundPituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated.MethodsThe SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient’s clinical and pathological features were considered.ResultsThe SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors.ConclusionThe study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

Background: most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. We investigated thyroid status and GH/IGF-1 in CeH in untreated patients with pituitary non-functioning and GH-secreting adenomas. Methods: This was a retrospective cross-sectional study of cases collected from two Hospitals between 2007 and 2016. One hundred-thirty-nine cases of non-functioning (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. correlations between the thyroid status, several clinicopathological parameters, and GH/IGF-1 were examined. Findings: Twenty-four percent of NFPA patients had CeH. severity did not correlate with tumor size and age, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; about half had normal TSH levels and about half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in NFPA patients. One-fourth of GHPA patients had normal FT4 levels and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. Interpretation: 1) NFPA patients with CeH had TSH levels within a normal range. 2) GHPA patients were resistant to CeH, which may be a result of stimulated thyroid function by GH/IGF-1. 3) We found an age-dependent decrease in serum IGF-1 levels in a large cohort of GHPAs. Funding Statement: This work was supported by JSPS KAKENHI Grants 16K15493, 23591345, and 20591087 (to M.Y.) and 16K19551 (to K.H.). This work was partially supported by the Advancing Care of Hypothalamic-Pituitary Dysfunction in Japan Study (to M.Y.) from the Japan Agency for Medical Research and Development, and the Research on Rare and Intractable Disease, Health and Labour Sciences Research Grants (to M.Y.). Declaration of Interests: authors state: The authors have nothing to disclose. Ethics Approval Statement: studies were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Ethics Committee on human research of Gunma University (Approval number 535: Gunma University Human Genome Ethics Committee).

Objective: To study the relationship between histopathology and clinical prognosis of invasive pituitary adenoma subjected to transsphenoidal surgery. Methods: The enrolled were 82 patients with invasive pituitary adenomas undergoing transsphenoidal surgery during Jan. 2000 -- May 2003 in our department with full MR imaging findings, pathology data and follow-up information. The follow-up duration was 5--30 months. Results: MR imaging findings of invasive pituitary adenoma included: depression of the sellar floor, involvement of sphenoid sinus and cavernous sinus, breakthrough of diaphragma sellae, encasement of internal carotid artery, etc. Pathological examination revealed that the invasion rate of dura in sella turcica was the highest among the structures around tumor. Pituitary adenoma apoplexy was found in 20 cases (24.4%). The total removal rate for PRL-secreting adenomas was significantly lower than that for non-secreting adenomas (P<0.01), but non-, GH-, ACTH-secreting adenomas had no significant differences. The recurrence rate of PRL-secreting adenomas was higher than that of non- and GH-secreting adenomas (P<0.05). Conclusion: Among invasive pituitary adenomas, the therapeutic effects of nonand GH-secreting pituitary adenomas are better than that of PRL-secreting adenomas. Invasive biological behaviors of invasive pituitary adenomas result in radical operation failure and postoperative recurrence.

Background: Growth hormone (GH)-secreting pituitary adenomas can be divided into densely and sparsely granulated subtypes, based on electron microscopic studies. The latter are frequently associated with more invasive behavior, and respond worse to somatostatin analogues. The underlining mechanisms are largely unknown. Increasing evidence showed that N6-methyladenosine (m6A) of messenger RNAs (mRNAs) participated in the development of various tumors. We aimed to investigate the role of RNA m6A modification in the classification of GH-secreting pituitary adenomas. Methods: The main components of m6A methyltransferase complex, demethylase, and RNA m6A levels were compared between sparsely and densely GH-secreting tumors. The role of METTL3 was functionally studied. Results: The level of m6A methyltransferases (METTL3, WTAP and METTL14) and demethylase (FTO and ALKBH5) were significantly downregulated in GH adenomas, comparing to the normal pituitary tissues. However, only METTL3 and METTL14 were shown to significantly higher in densely granulated tumors than those in sparsely ones. Consistently, the level of RNA m6A was markedly increased in densely granulated GH adenomas. In addition, the expression of METTL3 was positively correlated with the level of RNA m6A among tumor samples, and METTL3 silencing decreased RNA m6A of GH3 cells. METTL3 was demonstrated to function as a tumor suppressor based on in vivo and in vitro evidence, using patient-derived and GH3 cells. Moreover, the sensitivity of GH3 cells to pasireotide was increased with METTL3 overexpression, but decreased when METTL3 was silenced. Consistently, METTL3 silencing inhibited GH secretory, and decreased the expression of SSTR2 and SSTR5. Conclusions: METTL3 functions as a tumor suppressor in GH secreting adenomas, and enhance tumor cells sensitivity to medical treatment. Our work uncovers the critical roles of METTL3 in the pathogenesis of GH adenomas, since it potentially promotes the transition from sparsely to densely granulated subtypes.